7-Trifluorome thylsulfinylacetamido cephalosporins

ABSTRACT

Cephalosporin compounds having a trifluoromethylsulfinylacetamido group at the 7-position and various groups at the 3-position are prepared by acylation of a 7-aminocephalosporanic acid. The compounds have anti-bacterial activity.

United States Patent De Marinis et a1.

7-TRIFLUOROME THYLSULFINYLACETAMIDO C EPHALOSPORINS lnventorsi Robert M.De Marinis, King of Prussia; John R. E. Hoover, Glenside, both of Pa.

SmithKline Corporation, Philadelphia, Pa.

Filed: June 18, 1973 Appl. No.: 371,081

Assignee:

US. Cl. 260/243 C; 424/246 Int. Cl C07d 99/24 Field of Search 260/243 CReferences Cited UNITED STATES PATENTS 1/1967 Flynn 260/243 C PrimaryExaminer-Nicholas S, Rizzo Attorney, Agent, or FirmA1an D. Lourie;William H. Edgerton [57] ABSTRACT Cephalosporin compounds having atrifluoromethylsulfinylacetamido group at the 7-position and variousgroups at the 3-position are prepared by acylation of a7-aminocephalosporanic acid. The compounds have anti-bacterial activity.

5 Claims, No Drawings 7-TRIFLUOROME THYLSULFINYLACETAMIDO CEPHALOSPORINSThis invention relates to cephalosporin compounds which haveantibacterial activity. In particular, the invention relates tocompounds having a trifluoromethylsulfinylacetamido substituent atposition 7 of the cephem nucleus.

The compounds of this invention are represented by the followingstructural formula:

CF CH2CONH in which:

M is hydrogen or an alkali metal or ammonium cation;

A is hydrogen, methyl, acetoxymethyl, pyridiniummethyl, CH SHet, CH SR'or CH OR', where R is hydrogen or alkyl of from one to four carbonatoms; and

Het is a five or six membered heterocyclic group containing carbon andone to four atoms selected from the group consisting of N, O and S, eachsuch group being unsubstituted or substituted with from one to twogroups selected from lower alkyl, alkoxyalkyl, and trifluorometliyl,each alkyl or alkoxy group having from one to four carbon atoms, or anN-oxide thereof.

Preferred compounds are those where A is acetoxymethyl or CH SHet.Particularly preferred as those compounds where Het is unsubstituted ormethyl substituted 1,2,3-triazolyl, 1,2,4-triazolyl, l,2,3,4-tetrazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,3,4- thiadiazolyl,or 1,2,4-thiadiazolyl.

Included within the scope of this invention are the pharmaceuticallyacceptable salts that are formed by reaction of the cephalosporanic acidwith a pharmaceutically acceptable base.

Cephalosporins with a wide variety of acyl groups at position 7 of thecephem nucleus have been disclosed in the prior art, including many 7-alkylmercaptoacetamidocephalosporanic acid derivatives (US. Pat. Nos.3,573,298, 3,297,692 and others). 7-Substitutedalkylsulfinylacetamidocephalosporanic acids variously substituted atposition 3 (but not with CH SHet) are described in US. Pat. No.3,382,238 and German Pat. No. 2,000,878. Our own copending applicationSer. No. 273,571, filed July 20, 1972, now US. Pat. No. 3,828,037discloses 7-trifluoromethylmercaptoacetamidocephalosporins. However, nocephalosporins with a trifluoromethylsulfinyl group in the 7-acylsubstituent are known.

The compounds of this invention are prepared by acylation of theappropriately substituted 7-aminocephalosporanic acid withtrifluoromethylsulfinylacetic acid. The carboxyl group of the acylatingagent may be activated by one of the methods known in the art such asthe mixed anhydride. acid halide, or activated ester. 1n additioin,acylation of esters of the cephalosporin nucleus may be done by use of acoupling reagent such as dicyclohexylcarbodiimide.

Following the acylation, the protective groups can be removed with anacid such as trifluoroacetic acid.

The compounds are also prepared by displacement of a 7-acylated.3-acetoxymethylcephalosporin with a mercaptoheterocycle in an aqueous,slightly basic medium.

Trifluoromethylsulfinylacetic acid is prepared by hydrogen peroxideoxidation of trifluoromethylmercaptoacetic acid according to knownprocedures [Zh. Obshch. Khim. 35, 9, 1628 (1965)].

The compounds of this invention have antibacterial activity against bothGram-positive and Gram-negative organisms. Minimum inhibitoryconcentrations (MICs) ranged from 0.1 to 200 ug/ml in in vitro testing.These results are shown below for 7-trifluoromethylsulfinylacetamido-3-acetoxymethyl-3- cephem-4-carboxylicacid (1) and 7- trifluoromethylsulfinylacetamido-3-( l-methyl-l ,2 ,3,4- tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid (11). Whenadministered in vivo (s.c.), compound 1 showed an ED of 29 mg/kg againstE. coli and 200 mg/kg against Klebs. pneumo. The ED for compound 11against e. coil was 4.6-22 mg/kg; against Klebs. pneumo. it was 50-56mg/kg.

TABLE 1 MlC (#g/ml) Bacteria l 11 S. aureus HH 127 1.6 0.8 S. aureux SK23390 1.6 0.8 Strep. pyog. C203 0.2 0.1 Strep. faecalis HH 34358 100 100E. coli SK 12140 6.3 0.8 E. coli HH 33779 12.5 1.6 K1017. pneumo. SK4200 3.1 0.8 Kleb. pneumo. SK 1200 3.1 0.8 Pst'udomonas sp. HH 63 200200 Salmonella 3.1 0.4 Shigella 6.3 0.4 Emeru. aerogenes 50 1.6 Serraliamare. ATCC 13880 200 200 S. villaluz SK 70390 100 50 Enrero. cloaca HH31254 12.5

These compounds are formulated and administered by injection in doses of250-500 mg in the same manner as other cephalosporins. The precisedosages are dependent upon the age and weight of the subject and on thenature of the infection being treated. Determination of dosages iswithin the skill of the art.

The following examples illustrate the invention, but are not to beconstrued as limiting the scope thereof. Temperatures are in degreesCentigrade unless otherwise stated.

EXAMPLE 1 7-Trifluoromethylsulfinylacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acidtrifluoromethylsulfinylacetamido-3-acetoxymethyl-3- cephem-4-carboxy1icacid as a gum which was then dissolved in 50 ml of ethyl acetate. Thesolution was filtered and to the filtrate was added with stirring 1.5 mlof a 30% solution of sodium 2-ethylhexarioate in isopropanol. Dropwiseaddition of the resultant solution to 200 ml of pet ether causedprecipitation of the sodium salt (0.515 g, 73%) which was collected andpurified by solution in 5 ml of acetonitrile and addition of thissolution to 100 ml of rapidly stirred ether. The preciptate wascollected, washed with ether and dried in vacuo to give 0.370 g of puresalt.

C H F N O,S .Na.1 H O.1 CF CO H (584.424)

7-Amino-3-( l-methyl- 1 ,2,3 ,4-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid To a suspension of 27.2 g (0.1 mol) of 7-ACAin 200 ml of water and 100 ml of acetone was added a solution of 18.9 gof sodium bicarbonate in 200 ml of water. The resultant solution waswarmed on a steam bath and a solution of 14.5 g (0.125 mol) ofl-methyl-S-mercaptol,2,3,4-tetrazole in 200 ml of acetone was added. Thereaction mixture was refluxed for 3.5 hr. while maintaining the pH at7.48.0 by addition of 5% sodium bicarbonate. Acidification of the cooledreaction mixture to pH 3.5 with 6N hydrochloric acid resulted inprecipitation of 7-amino-3-( l-methyll ,2,3,4-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, which was collected, washedwith water and air dried (16 g, 49%).

EXAMPLE 3 7-Trifluoromethylsulfiny1acetamido-3-( l-methyl- 1 ,2,3,4-tetrazol-5ylthiomethyl )-3-cephem-4- carboxylic acid To a solution of1.54 g (0.004 mol) of 7-amino-3-(1- methyl-1,2,3,4-tetrazol-5-ylthiomethyl )-3-cephem-4- carboxylic acid; t-butylester and 0.825 g (0.004 mol) of dicyclohexylcarbodiimide in 50 ml ofbenzene was added 0.704 g (0.004 mol) of trifluoromethylsulfinylaceticacid. The reaction mixture was stirred at 25 for 2 hr., then it wasfiltered and adsorbed onto 4 g of silica gel. Chromatography on 100 g ofsilica gel with 50:50 benzene-ethyl acetate gave 1.55 g (69%) of 7-trifluoromethylsulfinylacetamido-3-( l-methyl-l ,2,3,4-tetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid, t-butyl ester as awhite foam. The ester was dissolved in 9 m1 of trifluoroacetic acid andstirred at 25 for 5 minutes, then added dropwise to 200 ml of ether. Theprecipitate was collected, dissolved in 5% sodium bicarbonate and thesolution was diluted to 150 ml. After extraction with ethyl acetate theaqueous phase was acidified to pH 1.5 and extracted thrice more withethyl acetate. The combined extracts were dried (MgSO and concentratedto 35 ml, to whichre s'idue (the free acid) was added a solution of 1.5oF30% sodium 2- ethylhexanoate i n isopropanol followed"by 200 ml of :1

ether. The precipitated salt was collected, re-

precipitated from methanol-ether and dried in vacuo to give 0.680 g ofproduct.

C H F N O S .Na. /2 H O (517.484)

7-Trifluoromethylsulfinylacetamido-3-( l ,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid To a solution of3.1 g (0.009 mol) of 7-amino-3-l,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4- carboxylic acid in ml of 3%aqueous sodium bicarbonate is added 60 ml of acetone. The solution iscooled to -l5 and 1.94 g (0.010 mol) of trifluoromethylsulfinylacetylchloride in 20 ml of acetone is added over a 10-minute period. Thereaction mixture is stirred at -l5 for 30 minutes while maintaining thepH at 7.6-8.0 by addition of 10% sodium hydroxide, then at 25 for 1hour. The reaction mixture is extracted once with ether and the aqueousphase is acidified to pH 2.5 with dilute hydrochloric acid and extractedwith ethyl acetate. The organic extracts are dried (MgSO andconcentrated in vacuo to give the title compound.

EXAMPLE 5 When either an equivalent amount of a 7-amino-3-heterocyclicthiomethyl-3-cephem-4-carboxylic acid (prepared by theprocedure of Example 2) listed below is substituted into the procedureof Example 4 for 7- amino-3-( l,3,4-thiadiazol-2-ylthiomethyl)-3-cephem- 4-carboxy1ic acid or its t-butyl ester is substituted intothe procedure of Example 3 for 7-amino-3-(1-methyl- 1 ,2,3,4-tetrazol-5ylthiomethyl )-3-cephem-4- carboxylic acid, t-butyl ester,the appropriate 7- trifluoromethylsulfinylacetamido-3-heterocyclicthiomethyl-3-cephem-4-carboxylic acid is obtained.

7-amino-3-(5-methy1-1,3 ,4-thiadiazo1-2-ylthiomethyl)-3-cephem-4-carboxylic acid 7-amino-3-( 5'-ethyl- 1 ,3,4-thiadiazol-2-ylthiomethyl 3-cephem-4-carboxylic acid7-amino-3-(S-trifluoromethyl-l ,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid 7-amino-3-( S-n-butyl-l ,3,4-thiadiazol-2- ylthiomethyl)-3-cephem-4-carboxylic acid 7-amino-3-( 1,2,4-thiadiazol-5ylthiomethyl )-3- cephem-4-carboxylic acid7-amino-3-(3-methyl-1 ,2,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxy1ic acid 7-amino-3-( 3-ethyl-l,2,4-thiadiazol-5ylthiomethyl 3-cephem-4-carboxylic acid7-amino-3-(thiazol-5-y1thiomethyl)-3-cephem-4- carboxylic acid7-amino-3-( 2-methy1thiazol-5-ylthiomethyl )-3- cephem-4-carboxylic acid7-amino-3-(4-methylthiazol-S-ylthiomethyl)-3- cephem-4-carboxylic acid7-amino-3-(2,4-dimethylthiazol-5ylthiomethyl)-3- cephem-4-carboxylicacid ,7-amino-3-( 2-ethylthiazol-5ylthiomethyl )-3- cephem-4-carboxy1icacid cording to the procedure of Example 1 gives the title compound.

EXAMPLE l 7-Trifluoromethylsulfinylacetamido- 3-cephem-4- carboxylicacid A solution of 0.78 g (2 mmol) of benzhydryl 7-amino-3-cephem-4-carboxylate (South African Pat. No. 71/067 19), 0.35 g(2 mmol) of trifluoromethylsulfinylacetic acid and 0.4 g (2 mmol) ofdicyclohexylcarbodiimide in dry tetrahydrofuran (15 ml) is stirred atroom temperature overnight. The precipitate is collected and washed withtetrahydrofuran and the combined filtrate and washings are evaporated invacuo. The residue is treated with a cold solution of trifluoroaceticacid (10 ml) and anisole (0.5 g) for minutes and then concentrated invacuo. The residue is dissolved in ethyl acetate and treated with 5%aqueous sodium bicarbonate. The aqueous phase is adjusted to pH 2 andthe precipitated product is collected and dried.

EXAMPLE 1 l An injectable pharmaceutical composition is formed by addingsterile water or sterile saline solution (2 ml) to 500 mg of7-trifluoromethylsulfinylacetamido-3-( lmethyl-l ,2,3,4-tetrazol-5-ylthiomethyl)-3-cephem-4- carboxylic acid, sodium slt.

Pharmaceutical compositions of the other antibacterial compoundsdescribed by Formula I or disclosed in the above examples may beformulated in a similar manner.

We claim:

1. A compound of the formula:

COOM

in which:

M is hydrogen or an alkali metal or ammonium cation;

A is CH Sl-let; and

Het is a five or six membered heterocyclic group containing carbon andone to four atoms selected from the group consisting of N, O and S, eachsuch group being unsubstituted or substituted with from one to twogroups selected from lower alkyl, alkoxyalkyl, and trifluoromethyl, eachalkyl or alkoxy having from one to four carbon atoms, or an N- oxidethereof.

2. A compound as claimed in claim 1 where Het is triazolyl, tetrazolyl,oxazolyl, thiazolyl, or thiadiazolyl, each Het group being unsubstitutedor substituted with one or two alkyl groups of from one to four carbonatoms.

3. A compound as claimed in claim 2, being the compound7-trifluoromethylsulfinylacetamido-3-( lmethyl-l,2,3,4-tetrazol-5-ylthiomethyl)-3-cephem-4- carboxylic acid.

4. A compound as claimed in claim 2, being the compound7-trifluoromethylsulfinylacetamido-3-( 5- methyl-1 ,3,4-thiadiazol-2-ylthiomethyl )-3-cephem-4- carboxylic acid.

5. A compound as claimed in claim 2, being the compound7-trifluoromethylsulfinylacetamido-3-( 1,2,3-

triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid.

1. A COMPOUND OF THE FORMULA:
 2. A compound as claimed in claim 1 whereHet is triazolyl, tetrazolyl, oxazolyl, thiazolyl, or thiadiazolyl, eachHet group being unsubstituted or substituted with one or two alkylgroups of from one to four carbon atoms.
 3. A compound as claimed inclaim 2, being the compound7-trifluoromethylsulfinylacetamido-3-(1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
 4. A compound as claimed inclaim 2, being the compound7-trifluoromethylsulfinylacetamido-3-(5-methyl-1,3,4-thiadiazol-2-ylthioMethyl)-3-cephem-4-carboxylic acid.
 5. A compound as claimed inclaim 2, being the compound7-trifluoromethylsulfinylacetamido-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid.